Association of apolipoprotein E variation with cognitive impairment across multiple neurodegenerative diagnoses

Dilliott, Allison A.; Sunderland, Kelly M; McLaughlin, Paula; Roberts, Angela; Evans, Emily C; Abrahão, Agessandro; Binns, Malcolm A.; Black, Sandra E.; Borrie, Michael; Casaubon, Leanne K.; Dowlatshahi, Dar; Finger, Elizabeth; Fischer, Corinne E.; Frank, Andrew; Freedman, Morris; Grimes, David A.; Hassan, Ayman; Jog, Mandar; Kumar, Sanjeev; Kwan, Donna; Lang, Anthony E.; Mandzia, Jennifer; Marras, Connie; Masellis, Mario; McIntyre, Adam D.; Pasternak, Stephen; Pollock, Bruce G.; Rajji, Tarek K.; Robinson, John F.; Rogaeva, Ekaterina; Sahlas, Demetrios J.; Saposnik, Gustavo; Sato, Christine; Seitz, Dallas; Shoesmith, Christen; Steeves, Thomas; Strother, Stephen C.; Swartz, Richard H.; Tan, Brian; Tang‐Wai, David F.; Tartaglia, Maria Carmela; Troyer, Angela K.; Turnbull, John; Zinman, Lorne; Investigators, Ondri; Hegele, Robert A.

doi:10.1016/j.neurobiolaging.2021.04.011

Cited by 11 publications

(10 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This project will build upon our previous studies applying novel concepts from behavioral economics and Neuroeconomics ( 35 , 42 , 46 – 48 , 53 – 56 ) and advance our knowledge on: (1) factors associated with practice gaps in the management of patients with dementia by PCPs across Canada; and (2) how the introduction of a DMT would modify treatment gaps. For example, we expect to estimate the the frequency of treatment initiation for case-scenarios with mild, moderate and advance AD, the use CSF diagnostic tests and new therapies (e.g., aducanumab) by PCPs.…”

Section: Expected Results and Future Directionsmentioning

confidence: 99%

Decision making under uncertainty in the diagnosis and management of Alzheimer's Disease in primary care: A study protocol applying concepts from neuroeconomics

et al. 2022

Self Cite

View full text Add to dashboard Cite

BackgroundThe current management of patients with Dementia, primarily with Alzheimer's Disease (AD) is rapidly evolving. However, limited information is available about the current gaps and decision-making in primary care.ObjectivesTo evaluate factors associated with gaps, risk preferences regarding diagnostic and therapeutic choices in the management of patients with AD by primary care physicians (PCP) from across Canada.MethodsWe propose a non-interventional, cross-sectional pilot study involving 120 primary care physicians referred from the College of Family Physicians of Canada to assess diagnostic and therapeutic decisions in the management of ten simulated AD-related case-scenarios commonly encountered in clinical practice. We initially describe the current landscape and gaps regarding diagnostic and therapeutic challenges in the management of patients with AD in primary care. Then, we provide concepts from behavioral economics and neuroeconomics applied to medical decision-making. Specifically, we include standardized tests to measure risk aversion, physicians' reactions to uncertainty, and questions related to risk preferences in different domains. Finally, we summarize the protocol to be implemented to address our goals. The primary study outcome is the proportion of participants that elect to defer initial investigations to the specialist and the associated factors. Secondary outcomes include the proportion of PCP willing to order cerebral spinal fluid studies, PET scans, or initiate treatment according to the simulated case-scenarios. The study will be conducted in English and French.ConclusionsThe study findings will contribute a better understanding of relevant factors associated with diagnostic and therapeutic decisions of PCP in the management of AD, identifying participant's preferences and evaluating the role of behavioral aspects such tolerance to uncertainty, aversion to ambiguity, and therapeutic inertia.

show abstract

Section: Expected Results and Future Directionsmentioning

confidence: 99%

Decision making under uncertainty in the diagnosis and management of Alzheimer's Disease in primary care: A study protocol applying concepts from neuroeconomics

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…A recent longitudinal genome-wide survival study not only confirmed the notion of an association between APOE and cognition in PD, but demonstrated a substantial aggregate association of polygenic progression scores (but not polygenic susceptibility scores) with dementia risk, and proposed diverging genetic architectures of cognitive disease progression and susceptibility 27 . The pathophysiologic basis for APOE ε4 and ε2 as risk and protective factors, respectively, for cognitive decline in neurodegenerative disorders have yet to be clearly elucidated although clues to biologically plausible mechanism are emerging 28 – 30 . APOE protein structure (and function) varies per allele due to the single amino acid substitutions that result in greater inherent stability in ε2, which also confers less domain specific interactions that deter neurodegenerative processes (such as amyloid-related damage, synaptic dysfunction, oxidation and inflammation) in contrast to ε4 28 , 29 .…”

Section: Discussionmentioning

confidence: 99%

APOE E4 is associated with impaired self-declared cognition but not disease risk or age of onset in Nigerians with Parkinson’s disease

Okubadejo

Okunoye

Ojo

et al. 2022

npj Parkinsons Dis.

View full text Add to dashboard Cite

The relationship between APOE polymorphisms and Parkinson’s disease (PD) in black Africans has not been previously investigated. We evaluated the association between APOE polymorphic variability and self-declared cognition in 1100 Nigerians with PD and 1097 age-matched healthy controls. Cognition in PD was assessed using the single item cognition question (item 1.1) of the MDS-UPDRS. APOE genotype and allele frequencies did not differ between PD and controls (p > 0.05). No allelic or genotypic association was observed between APOE and age at onset of PD. In PD, APOE ε4/ε4 conferred a two-fold risk of cognitive impairment compared to one or no ε4 (HR: 2.09 (95% CI: 1.13–3.89; p = 0.02)), while APOE ε2 was associated with modest protection against cognitive impairment (HR: 0.41 (95% CI 0.19–0.99, p = 0.02)). Of 773 PD with motor phenotype and APOE characterized, tremor-dominant (TD) phenotype predominated significantly in ε2 carriers (87/135, 64.4%) compared to 22.2% in persons with postural instability/gait difficulty (PIGD) (30/135) and 13.3% in indeterminate (ID) (18/135, 13.3%) (p = 0.037). Although the frequency of the TD phenotype was highest in homozygous ε2 carriers (85.7%), the distribution of motor phenotypes across the six genotypes did not differ significantly (p = 0.18). Altogether, our findings support previous studies in other ethnicities, implying a role for APOE ε4 and ε2 as risk and protective factors, respectively, for cognitive impairment in PD.

show abstract

“…The E3 is the most prevalent and has a frequency of approximately 80%. The E4 may be found in up to 20% of the population and was associated with a higher risk of Alzheimer’s dementia (AD), whereas the rarest E2 was linked with a lower risk of cognitive decline ( Paul et al, 2016 ; Iwaki et al, 2019b ; Dilliott et al, 2021 ; Tipton et al, 2021 ; Counsell et al, 2022 ; Li et al, 2022 ). Previous studies have demonstrated that patients with PD and at least one E4 allele are at increased risk of cognitive deterioration ( Paul et al, 2016 ; Iwaki et al, 2019b ; Dilliott et al, 2021 ; Tipton et al, 2021 ; Counsell et al, 2022 ; Li et al, 2022 ).…”

Section: Genetic Risk Factors Associated With Parkinson’s Disease Sym...mentioning

confidence: 99%

“…The E4 may be found in up to 20% of the population and was associated with a higher risk of Alzheimer’s dementia (AD), whereas the rarest E2 was linked with a lower risk of cognitive decline ( Paul et al, 2016 ; Iwaki et al, 2019b ; Dilliott et al, 2021 ; Tipton et al, 2021 ; Counsell et al, 2022 ; Li et al, 2022 ). Previous studies have demonstrated that patients with PD and at least one E4 allele are at increased risk of cognitive deterioration ( Paul et al, 2016 ; Iwaki et al, 2019b ; Dilliott et al, 2021 ; Tipton et al, 2021 ; Counsell et al, 2022 ; Li et al, 2022 ). However, contrary to AD, the protective effect of E2 on cognition was not confirmed in PD, and some showed that it might even increase the risk of PD and atypical parkinsonisms ( Dilliott et al, 2021 ; Li et al, 2022 ).…”

Section: Genetic Risk Factors Associated With Parkinson’s Disease Sym...mentioning

confidence: 99%

“…Previous studies have demonstrated that patients with PD and at least one E4 allele are at increased risk of cognitive deterioration ( Paul et al, 2016 ; Iwaki et al, 2019b ; Dilliott et al, 2021 ; Tipton et al, 2021 ; Counsell et al, 2022 ; Li et al, 2022 ). However, contrary to AD, the protective effect of E2 on cognition was not confirmed in PD, and some showed that it might even increase the risk of PD and atypical parkinsonisms ( Dilliott et al, 2021 ; Li et al, 2022 ). The MTHFR gene and its implications and in PD were discussed in-depth above.…”

Section: Genetic Risk Factors Associated With Parkinson’s Disease Sym...mentioning

confidence: 99%

See 1 more Smart Citation

Genetic architecture of Parkinson’s disease subtypes – Review of the literature

Dulski

Uitti²,

Ross³

et al. 2022

Front. Aging Neurosci.

View full text Add to dashboard Cite

The heterogeneity of Parkinson’s disease (PD) has been recognized since its description by James Parkinson over 200 years ago. The complexity of motor and non-motor PD manifestations has led to many attempts of PD subtyping with different prognostic outcomes; however, the pathophysiological foundations of PD heterogeneity remain elusive. Genetic contributions to PD may be informative in understanding the underpinnings of PD subtypes. As such, recognizing genotype-phenotype associations may be crucial for successful gene therapy. We review the state of knowledge on the genetic architecture underlying PD subtypes, discussing the monogenic forms, as well as oligo- and polygenic risk factors associated with various PD subtypes. Based on our review, we argue for the unification of PD subtyping classifications, the dichotomy of studies on genetic factors and genetic modifiers of PD, and replication of results from previous studies.

show abstract

Association of apolipoprotein E variation with cognitive impairment across multiple neurodegenerative diagnoses

Cited by 11 publications

References 43 publications

Decision making under uncertainty in the diagnosis and management of Alzheimer's Disease in primary care: A study protocol applying concepts from neuroeconomics

Decision making under uncertainty in the diagnosis and management of Alzheimer's Disease in primary care: A study protocol applying concepts from neuroeconomics

APOE E4 is associated with impaired self-declared cognition but not disease risk or age of onset in Nigerians with Parkinson’s disease

Genetic architecture of Parkinson’s disease subtypes – Review of the literature

Contact Info

Product

Resources

About